7-Substituted 8-aza-7-deazaadenosines for modification of the siRNA major groove

Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, USA.
Organic & Biomolecular Chemistry (Impact Factor: 3.56). 07/2012; 10(32):6491-7. DOI: 10.1039/c2ob25647a
Source: PubMed


Here we describe the synthesis of new 7-substituted 8-aza-7-deazaadenosine ribonucleoside phosphoramidites and their use in generating major groove-modified duplex RNAs. A 7-ethynyl analog leads to further structural diversification of the RNA via post-automated RNA synthesis azide-alkyne cycloaddition reactions. In addition, we report preliminary studies on the effects of eight different purine 7-position modifications on RNA duplex stability and pairing specificity. Finally, the effect on RNAi activity of this type of modification at eight different positions in an siRNA guide strand has been explored. Analogs were identified with large 7-position substituents that maintain adenosine pairing specificity and are well-tolerated at specific positions in an siRNA guide strand.

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